Chronic exposure of VEGF inhibitors promotes the malignant phenotype of colorectal cancer cells

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Author(s)

    • Tomida Chisato
    • Department of Physiological Nutrition, Institute of Health Biosciences, The University of Tokushima Graduate School
    • Teshima-Kondo Shigetada
    • Department of Physiological Nutrition, Institute of Health Biosciences, The University of Tokushima Graduate School
    • Yamagishi Naoko
    • Department of Physiological Nutrition, Institute of Health Biosciences, The University of Tokushima Graduate School
    • Aibara Kana
    • Department of Physiological Nutrition, Institute of Health Biosciences, The University of Tokushima Graduate School
    • Yano Chiaki
    • Department of Physiological Nutrition, Institute of Health Biosciences, The University of Tokushima Graduate School
    • Uchida Takayuki
    • Department of Physiological Nutrition, Institute of Health Biosciences, The University of Tokushima Graduate School
    • Abe Tomoki
    • Department of Physiological Nutrition, Institute of Health Biosciences, The University of Tokushima Graduate School
    • Ohno Ayako
    • Department of Physiological Nutrition, Institute of Health Biosciences, The University of Tokushima Graduate School
    • Hirasaka Katsuya
    • Graduate school of Fisheries Science and Environmental Studies, Nagasaki University
    • Nikawa Takeshi
    • Department of Physiological Nutrition, Institute of Health Biosciences, The University of Tokushima Graduate School

Abstract

VEGF-targeting anti-angiogenic drugs have enabled significant advances in cancer therapy. However, acquired resistance to VEGF-targeting drugs occurs, leading to disease progression. How tumors become the resistance remains fully uncertain. One of possible mechanisms for the resistance may be the direct effect of VEGF inhibitors on tumor cells expressing VEGF receptors (VEGF-R). We investigated here the direct effect of chronic VEGF inhibition on phenotype changes in cancer cells. To chronically inhibit cancer cell-derived VEGF, human colon cancer HCT116 cells were chronically exposed (3 months) to anti-VEGF neutralizing monoclonal antibody (HCT/mAb cells, blockade of VEGF alone) or VEGF-R tyrosine kinase inhibitor foretinib (HCT/fore cells, blockade of all VEGF family). HCT/mAb cells redundantly increased VEGF family member (VEGF, PlGF, VEGF-B, VEGF-R1 and VEGF-R2) and induced a resistance to hypoxia-induced apoptosis. By contrast, HCT/fore cells did not show the redundant increase in VEGF family member, but significantly increased a VEGF-independent pro-angiogenic factor FGF-2. HCT/fore cells showed increased migration and invasion activities in addition to a resistance to hypoxia-induced apoptosis. The resistance to apoptosis was significantly suppressed by inhibition of hypoxia-inducible factor-1α in HCT/mAb cells, but not in HCT/fore cells. These findings suggest that chronic inhibition of VEGF/VEGF-R accelerates malignant phenotypes of colon cancer cells. J. Med. Invest. 62: 75-79, February, 2015

Journal

  • The Journal of Medical Investigation

    The Journal of Medical Investigation 62(1.2), 75-79, 2015

    Faculty of Medicine Tokushima University

Codes

  • NII Article ID (NAID)
    130005129700
  • NII NACSIS-CAT ID (NCID)
    AA11166929
  • Text Lang
    ENG
  • Article Type
    journal article
  • ISSN
    1343-1420
  • Data Source
    IR  J-STAGE 
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